Breakthrough pain is a feared symptom afflicting the majority of cancer patients at some point in their illness. It is characterized by rapid onset, with pain intensity reaching excruciating level within several minutes, and brief duration (median duration approximately 30 minutes). Although commonly used, due to their delayed onset and long duration of action, oral opioids do not relieve breakthrough pain adequately and often result in excess plasma drug concentration after the pain has subsided, thus introduce adverse effects. A recently approved oral transmucosal fentanyl product has been commercially successful by marginally accelerating the onset of breakthrough pain treatment relative to oral opioids. However, there remains a substantial unmet need for a faster onset treatment with minimal side effects. The goal of this proposal is to develop an inhalation device for rapid systemic delivery of fentanyl, a potent opioid analgesic, for the treatment of breakthrough pain. The inhalation device applies a novel technology pioneered by Alexza MDC to generate a pure fentanyl aerosol appropriate for systemic delivery through the deep lung. Preliminary animal studies have shown rapid, IV-like, systemic delivery of several FDA-approved drugs to dogs using our technology. In Phase I of this grant, we will demonstrate the feasibility of incorporating this aerosol generation technology into a handheld, multi-dose delivery device with features ensuring patient safety and minimizing opioid abuse and diversion. In Phase II, we will determine the safety of fentanyl inhalation in animal toxicology studies, design and manufacture devices for use in clinical trials, and complete all product testing required prior to human use of our device. By the end of the grant period, we will be ready to initiate human testing of the multi-dose device. Eventual FDA approval of our fentanyl product will allow cancer patients to relieve breakthrough pain more effectively, thus improving their overall quality of life. In addition, the secure, convenient multi-dose device platform for rapid systemic delivery will likely find other valuable applications in clinical practices.